XALKORI (crizotinib) capsules, for oral use Initial U.S. Approval: 2011

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XALKORI safely and effectively. See full prescribing information for XALKORI. XALKORI (crizotinib) capsules, for oral use Initial U.S. Approval: RECENT MAJOR CHANGES Dosage and Administration, Dosage Modifications for Moderate and Severe Hepatic Impairment (2.4) 2/ INDICATIONS AND USAGE XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS-positive as detected by an FDA-approved test (, 2.) DOSAGE AND ADMINISTRATION Recommended Dosage: 25 mg orally twice daily. (2.2) Moderate Hepatic Impairment: 2 mg orally twice daily. (2.4) Severe Hepatic Impairment: 25 mg orally once daily. (2.4) Severe Renal Impairment: 25 mg orally once daily. (2.5) DOSAGE FORMS AND STRENGTHS Capsules: 25 mg, 2 mg. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Hepatotoxicity: Fatal hepatotoxicity occurred in.% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.3, 5.) Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of patients. Permanently discontinue in patients with ILD/pneumonitis. (5.2) QT Interval Prolongation: Occurred in 2.% of patients. Monitor electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.3, 5.3) Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.3, 5.4) Severe Visual Loss: Reported in.2% of patients. Discontinue XALKORI in patients with severe visual loss. Perform an ophthalmological evaluation. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.6, 8., 8.3) ADVERSE REACTIONS The most common adverse reactions ( 25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at or FDA at -8-FDA-88 or DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use. (2.6, 7.) Strong CYP3A Inducers: Avoid concomitant use. (7.) CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious adverse reactions. (7.2) USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) See 7 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 2/28 FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2. Patient Selection 2.2 Recommended Dosage 2.3 Dosage Modification for Adverse Reactions 2.4 Dosage Modifications for Moderate and Severe Hepatic Impairment 2.5 Dosage Modifications for Severe Renal Impairment 2.6 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5. Hepatotoxicity 5.2 Interstitial Lung Disease/Pneumonitis 5.3 QT Interval Prolongation 5.4 Bradycardia 5.5 Severe Visual Loss 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6. Clinical Trials Experience 7 DRUG INTERACTIONS 7. Effect of Other Drugs on XALKORI 7.2 Effect of XALKORI on Other Drugs 7.3 Drugs That Prolong the QT Interval 7.4 Drugs That Cause Bradycardia 8 USE IN SPECIFIC POPULATIONS 8. Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment DESCRIPTION 2 CLINICAL PHARMACOLOGY 2. Mechanism of Action 2.2 Pharmacodynamics 2.3 Pharmacokinetics 3 NONCLINICAL TOXICOLOGY 3. Carcinogenesis, Mutagenesis, Impairment of Fertility 4 CLINICAL STUDIES 4. ALK-Positive Metastatic NSCLC 4.2 ROS-Positive Metastatic NSCLC 6 HOW SUPPLIED/STORAGE AND HANDLING 7 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

2 FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS-positive as detected by an FDA-approved test [see Dosage and Administration (2.)]. 2 DOSAGE AND ADMINISTRATION 2. Patient Selection Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS positivity in tumor specimens [see Clinical Studies (4., 4.2)]. Information on FDA-approved tests for the detection of ALK and ROS rearrangements in NSCLC is available at Recommended Dosage The recommended dosage of XALKORI is 25 mg orally twice daily, with or without food, until disease progression or no longer tolerated by the patient. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions are: First dose reduction: XALKORI 2 mg taken orally twice daily Second dose reduction: XALKORI 25 mg taken orally once daily Permanently discontinue if unable to tolerate XALKORI 25 mg taken orally once daily. Dosage modifications for adverse reactions for XALKORI are provided in Tables and 2. Table. XALKORI Dosage Modification Hematologic Toxicities a Severity of Adverse Reaction b XALKORI Dosage Modification Grade 3 Withhold until recovery to Grade 2 or less, then resume at the same dosage Grade 4 Withhold until recovery to Grade 2 or less, then resume at next lower dosage a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). b Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.. Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. 2

3 Table 2. XALKORI Dosage Modification Non-Hematologic Toxicities Severity of Adverse Reaction a XALKORI Dosage Modification Hepatotoxicity [see Warnings and Precautions (5.)] Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to.5 times ULN ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than.5 times ULN (in the absence of cholestasis or hemolysis) Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage. Permanently discontinue. Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)] Any grade drug-related interstitial lung disease/pneumonitis Permanently discontinue. QT Interval Prolongation [see Warnings and Precautions (5.3)] QT corrected for heart rate (QTc) greater than 5 ms on at least 2 separate electrocardiograms (ECGs) QTc greater than 5 ms or greater than or equal to 6 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Bradycardia [see Warnings and Precautions (5.4)] Bradycardia b (symptomatic, may be severe and medically significant, medical intervention indicated) Withhold until recovery to baseline or to a QTc less than 48 ms, then resume at next lower dosage. Permanently discontinue. Withhold until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Bradycardia b,c (life-threatening consequences, urgent intervention indicated) If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Permanently discontinue if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 25 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above, with frequent monitoring. Severe Vision Loss [see Warnings and Precautions (5.5)] Visual Loss (Grade 4 Ocular Disorder) Discontinue during evaluation of severe vision loss. a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.. b Heart rate less than 6 beats per minute (bpm). c Permanently discontinue for recurrence. 3

4 2.4 Dosage Modifications for Moderate and Severe Hepatic Impairment The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than.5 times the upper limit of normal (ULN) and less than or equal to 3 times ULN] is 2 mg orally twice daily. The recommended dose of XALKORI in patients with pre-existing severe hepatic impairment (any AST and total bilirubin greater than 3 times ULN) is 25 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (2.3)]. 2.5 Dosage Modifications for Severe Renal Impairment The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CL cr ) less than 3 ml/min, calculated using the modified Cockcroft-Gault equation] not requiring dialysis is 25 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (2.3)]. 2.6 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 25 mg orally once daily [see Drug Interactions (7.)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor. 3 DOSAGE FORMS AND STRENGTHS Capsules: 25 mg: hard gelatin capsule, size, pink opaque cap and body, with Pfizer on the cap and CRZ 25 on the body. 2 mg: hard gelatin capsule, size, white opaque body and pink opaque cap, with Pfizer on the cap and CRZ 2 on the body. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5. Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome occurred in.% of the 79 patients treated with XALKORI across clinical trials [see Adverse Reactions (6.)]. Concurrent elevations in ALT or AST 3 times the ULN and total bilirubin 2 times the ULN, with normal alkaline phosphatase, occurred in <% treated with XALKORI. Increased ALT or AST >5 times the ULN occurred in % and 6% of patients, respectively. One percent (.%) of patients required permanent discontinuation due to elevated transaminases. Increased transaminases generally occurred within the first 2 months of treatment. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage and Administration (2.3)]. 4

5 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=79), 2.9% of XALKORI-treated patients had ILD of any grade,.% had Grade 3 or 4 ILD, and.5% had fatal ILD [see Adverse Reactions (6.)]. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3)]. 5.3 QT Interval Prolongation QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 2.% of 66 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 5 ms and 5% of 582 patients had an increase from baseline QTcF greater than or equal to 6 ms by automated machine-read evaluation of ECGs. Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.3), Clinical Pharmacology (2.2)]. 5.4 Bradycardia Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 3% of 79 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORItreated patients and in.6% of the chemotherapy-treated patients [see Adverse Reactions (6.)]. Avoid using XALKORI in combination with other medications known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as recommended [see Dosage and Administration (2.3)]. 5.5 Severe Visual Loss Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was.2% of 79 patients [see Adverse Reactions (6.)]. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 2/2 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient. 5

6 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose. Advise males with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 9 days after the final dose [see Use in Specific Populations (8., 8.3), Nonclinical Toxicology (3.)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3)] Bradycardia [see Warnings and Precautions (5.4)] Severe Visual Loss [see Warnings and Precautions (5.5)] 6. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in the Warnings and Precautions reflect exposure to XALKORI in 79 patients who received XALKORI 25 mg twice daily enrolled on Studies (including an additional 9 patients who crossed over from the control arm), 2, 3, a single arm trial (n=63) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=54). The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 25 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies and 2). The safety of XALKORI was also evaluated in 5 patients with ROS-positive metastatic NSCLC from a single-arm study (Study 3). The most common adverse reactions ( 25%) of XALKORI are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. Previously Untreated ALK-Positive Metastatic NSCLC - Study (PROFILE 4) The data in Table 3 are derived from 34 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study ). Patients in the XALKORI arm (n=7) received XALKORI 25 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 69 patients in the chemotherapy arm received pemetrexed 5 mg/m 2 with cisplatin 75 mg/m 2 (n=9) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg min/ml (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, 6

7 patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression. The median duration of study treatment was.9 months for patients in the XALKORI arm and 4. months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 34 patients who were treated in Study, the median age was 53 years; 6% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian. Serious adverse events were reported in 34% of patients treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Dose reductions due to adverse reactions were required in 6% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (.8%) and elevated transaminases (.8%). Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (.2%), hepatotoxicity (.2%), and ILD (.2%). Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients. 7

8 Table 3. Adverse Reactions Reported at a Higher Incidence ( 5% Higher for All Grades or 2% Higher for Grades 3-4) with XALKORI than Chemotherapy in Study Adverse Reaction Cardiac Bradycardia a Electrocardiogram QT prolonged All Grades 4 6 XALKORI (N=7) Grade Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=69) All Grades 2 Grade 3-4 Eye Vision disorder b 7 Gastrointestinal Diarrhea Vomiting Constipation Abdominal pain c Dyspepsia Dysphagia Esophagitis d General Edema e Pyrexia Infections Upper respiratory infection f 32 2 Investigations Increased weight 8 2 Musculoskeletal and Connective Tissue Pain in extremity Muscle spasm Nervous System Dysgeusia Headache Dizziness g Adverse reactions were graded using NCI CTCAE version 4.. Includes cases reported within the clustered terms: a Bradycardia (Bradycardia, Sinus bradycardia). b Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment). c Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness). d Esophagitis (Esophagitis, Esophageal ulcer). e Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema). f g Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection). Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope). Additional adverse reactions occurring at an overall incidence between % and 6% in patients treated with XALKORI included nausea (56%), decreased appetite (3%), fatigue (29%), neuropathy (2%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash, renal cyst (5%), ILD (%; ILD, pneumonitis), syncope, and decreased blood testosterone (%; hypogonadism)

9 Table 4. Laboratory Abnormalities with Grade 3 or 4 Occurring in 4% of XALKORI-Treated Patients in Study XALKORI Chemotherapy Laboratory Abnormality Any Grade Grade 3-4 Any Grade Grade 3-4 Hematology Neutropenia Lymphopenia Chemistry Increased ALT Increased AST Hypophosphatemia Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4: %) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: %; Grade 4: %). Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 7) The data in Table 5 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=72) received XALKORI 25 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 7 patients in the chemotherapy arm received pemetrexed 5 mg/m 2 (n=99) or docetaxel 75 mg/m 2 (n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment. The median duration of study treatment was 7. months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least dose of study treatment), the median age was 5 years; 4% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian. Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis. Dose reductions due to adverse reactions were required in 6% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%). XALKORI was discontinued for adverse reactions in 5% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (.7%), increased ALT and AST (.2%), dyspnea (.2%), and pulmonary embolism (.2%). Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients. 9

10 Table 5. Adverse Reactions Reported at a Higher Incidence ( 5% Higher for All Grades or 2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 2 Adverse Reaction Nervous System Dysgeusia Dizziness a Syncope All Grades XALKORI (N=72) Grade Chemotherapy (Pemetrexed or Docetaxel) (N=7) All Grades 9 8 Grade 3-4 Eye Vision disorder b 6 9 Cardiac Electrocardiogram QT prolonged 5 Bradycardia c 5 Investigations Decreased weight 4 Gastrointestinal Diarrhea Nausea Vomiting Constipation Dyspepsia Infections Upper respiratory infection d 26 3 Respiratory, Thoracic and Mediastinal Pulmonary embolism e General Edema f 3 6 Adverse reactions were graded using NCI CTCAE version 4.. Includes cases reported within the clustered terms: a Dizziness (Balance disorder, Dizziness, Postural dizziness). b Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters). c Bradycardia (Bradycardia, Sinus bradycardia). d Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection). e Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism). f Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema). Additional adverse reactions occurring at an overall incidence between % and 3% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (9%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure, and decreased blood testosterone (%; hypogonadism)

11 Table 6. Laboratory Abnormalities with Grade 3 or 4 Occurring in 4% of XALKORI-Treated Patients in Study 2 XALKORI Chemotherapy Laboratory Abnormality Any Grade Grade 3-4 Any Grade Grade 3-4 Hematology Lymphopenia Neutropenia Chemistry Increased ALT Increased AST Hypophosphatemia Hypokalemia 8 4 Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 96%; Grade 3: %; Grade 4: %) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: %; Grade 4: %). ROS-Positive Metastatic NSCLC - Study 3 (PROFILE ) The safety profile of XALKORI from Study 3, which was evaluated in 5 patients with ROS-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=669). Vision disorders occurred in 92% of patients in Study 3; 9% were Grade and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months. Description of Selected Adverse Reactions Vision disorders Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 79 patients. The majority (95%) of these patients had Grade visual adverse reactions. There were.8% of patients with Grade 3 and.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies and 2 (>5%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to minute, and had mild or no impact (scores to 3 out of a maximum score of ) on daily activities as captured in the VSAQ-ALK questionnaire. Neuropathy Neuropathy, most commonly sensory in nature, occurred in 25% of 79 patients. Most events (95%) were Grade or Grade 2 in severity. Renal cysts Renal cysts were experienced by 3.% of 79 patients. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests. Renal toxicity The estimated glomerular filtration rate (egfr) decreased from a baseline median of ml/min/.73 m 2 (n=68) to a median of 8.23 ml/min/.73 m 2 at 2 weeks (n=499) in patients with ALK-positive advanced

12 NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median egfr from 2 to 4 weeks of treatment. Median egfr slightly increased (83.2 ml/min/.73 m 2 ) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in egfr to <9 ml/min/.73 m 2, 38% had a decrease to egfr to <6 ml/min/.73 m 2, and 3.6% had a decrease to egfr to <3 ml/min/.73 m 2. 7 DRUG INTERACTIONS 7. Effect of Other Drugs on XALKORI Strong or Moderate CYP3A Inhibitors Concomitant use of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (2.3)], which may increase the risk of adverse reactions of XALKORI. Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the XALKORI dosage [see Dosage and Administration (2.4)]. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Use caution with concomitant use of moderate CYP3A inhibitors. Strong CYP3A Inducers Concomitant use of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (2.3)], which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers. 7.2 Effect of XALKORI on Other Drugs CYP3A Substrates Concomitant use of crizotinib increases plasma concentrations of CYP3A substrates [see Clinical Pharmacology (2.3)], which may increase the risk of adverse reactions of these substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling. 7.3 Drugs That Prolong the QT Interval XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval [see Warnings and Precautions (5.3), Clinical Pharmacology (2.2)]. 7.4 Drugs That Cause Bradycardia XALKORI can cause bradycardia. Avoid concomitant use of XALKORI with drugs that cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) [see Warnings and Precautions (5.4)]. 2

13 8 USE IN SPECIFIC POPULATIONS 8. Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (2.)]. There are no available data on the use of XALKORI during pregnancy. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity (see Data). Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 5 to 2%, respectively. Data Animal Data Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses 5 mg/kg/day (approximately.6 times the recommended human dose based on AUC) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 2 mg/kg/day (approximately 2.7 times the recommended human dose based on AUC) or in rabbits at doses of up to 6 mg/kg/day (approximately.6 times the recommended human dose based on AUC), though fetal body weights were reduced at these doses. 8.2 Lactation Risk Summary There is no information regarding the presence of crizotinib or its metabolites in human milk, or the effects on the breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI [see Use in Specific Population (8.)]. Contraception XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.)]. Females Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days after the final dose. 3

14 Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 9 days after the final dose [see Nonclinical Toxicology (3.)]. Infertility Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (3.)]. 8.4 Pediatric Use The safety and effectiveness of XALKORI in pediatric patients have not been established. Juvenile Animal Toxicity Data Decreased bone formation in growing long bones was observed in immature rats at 5 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. 8.5 Geriatric Use Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=669), 6% were 65 years or older and 3.8% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical studies of XALKORI in patients with ROS-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin greater than.5 times ULN and less than or equal to 3 times ULN) or severe (any AST and total bilirubin greater than 3 times ULN) hepatic impairment [see Clinical Pharmacology (2.3)]. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2)]. No dose adjustment is recommended in patients with pre-existing mild hepatic impairment (AST > ULN and total bilirubin less than or equal to times ULN or any AST and total bilirubin greater than times ULN but less than or equal to.5 times ULN). 8.7 Renal Impairment Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment (CL cr less than 3 ml/min calculated using the modified Cockcroft-Gault equation) not requiring dialysis, therefore reduce dosage of XALKORI in these patients [see Dosage and Administration (2.4), Clinical Pharmacology (2.3)]. No dose adjustment is recommended in patients with mild to moderate renal impairment (CL cr 3 to 89 ml/min). 4

15 DESCRIPTION Crizotinib is a kinase inhibitor. The molecular formula for crizotinib is C 2 H 22 Cl 2 FN 5 O and the molecular weight is daltons. Crizotinib is described chemically as (R)-3-[-(2,6-Dichloro-3-fluorophenyl)ethoxy]- 5-[-(piperidin-4-yl)-H-pyrazol-4-yl]pyridin-2-amine. The chemical structure of crizotinib is shown below: NH N N Cl F CH 3 (R) Cl O N NH 2 Crizotinib is a white to pale-yellow powder with a pka of 9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of crizotinib in aqueous media decreases over the range ph.6 to ph 8.2 from greater than mg/ml to less than. mg/ml. The log of the distribution coefficient (octanol/water) at ph 7.4 is.65. XALKORI (crizotinib) for oral administration is supplied as printed hard-shell capsules containing 25 mg or 2 mg of crizotinib together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients. The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide. The white opaque capsule shell components contain gelatin and titanium dioxide. The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide. 2 CLINICAL PHARMACOLOGY 2. Mechanism of Action Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-met), ROS (c-ros), and Recepteur d Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS, and c-met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-met. 2.2 Pharmacodynamics Cardiac Electrophysiology In an ECG substudy conducted in 52 patients with ALK-positive NSCLC, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 2.3 ms (2-sided 9% upper CI: 9.5 ms) following 5

16 administration of XALKORI 25 mg orally twice daily. An exposure-qt analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see Warnings and Precautions (5.3)]. 2.3 Pharmacokinetics Following XALKORI 25 mg twice daily, steady-state was reached within 5 days and remained stable, with a median accumulation ratio of 4.8. Steady-state observed minimum concentration (C min ) and AUC increased in a greater than dose-proportional manner over the dose range of 2 mg to 3 mg twice daily (.8 to.2 times the approved recommended dosage). Absorption A single crizotinib dose was absorbed with median time to achieve peak concentration of 4 to 6 hours, and the mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%). Effect of Food A high-fat meal reduced crizotinib AUC -INF and maximum observed plasma concentration (C max ) by approximately 4%. Distribution The geometric mean volume of distribution (V ss ) of crizotinib was 772 L following a single intravenous dose. Protein binding of crizotinib is 9% and is independent of drug concentration in vitro. Crizotinib is a substrate for P-glycoprotein (P-gp) in vitro. The blood-to-plasma concentration ratio is approximately. Elimination The mean apparent plasma terminal half-life of crizotinib was 42 hours following single doses of crizotinib in patients. The mean apparent clearance (CL/F) of crizotinib was lower at steady-state (6 L/h) after 25 mg twice daily than after a single 25 mg oral dose ( L/h). Metabolism Crizotinib is predominantly metabolized by CYP3A. Excretion Following administration of a single oral 25 mg dose of radiolabeled crizotinib dose to healthy subjects, 63% (53% as unchanged) of the administered dose was recovered in feces and 22% (2.3% as unchanged) in urine. Specific Populations No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, ethnicity (Asian, non-asian), or body weight. Patients with Hepatic Impairment Steady-state mean crizotinib AUC and C max decreased by 9% in patients with mild hepatic impairment (AST >ULN and total bilirubin times ULN or any AST and total bilirubin > times ULN but.5 times ULN) compared to patients with normal hepatic function following XALKORI 25 mg orally twice daily. Steady-state mean crizotinib AUC increased by 4% and C max increased by 9% in patients with moderate hepatic impairment (any AST and total bilirubin >.5 times ULN and 3 times ULN) following XALKORI 6

17 2 mg orally twice daily compared with patients with normal hepatic function following XALKORI 25 mg orally twice daily. Mean crizotinib AUC decreased by 35% and C max decreased by 27% in patients with severe hepatic impairment (any AST and total bilirubin >3 times ULN) following XALKORI 25 mg orally once daily compared with patients with normal hepatic function following XALKORI 25 mg orally twice daily [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. Patients with Renal Impairment Mild or moderate renal impairment (CL cr of 6-89 ml/min or 3-59 ml/min, respectively, calculated using the modified Cockcroft-Gault equation) has no clinically significant effect on the exposure of crizotinib. Following a single 25 mg dose, the mean AUC -INF of crizotinib increased by 79% and the mean C max increased by 34% in patients with severe renal impairment (CL cr <3 ml/min) who did not require dialysis compared to those with normal renal function (CL cr 9 ml/min). Similar changes in AUC -INF and C max were observed for the active metabolite of crizotinib [see Dosage and Administration (2. 4), Use in Specific Populations (8.7)]. Drug Interaction Studies Clinical Studies Gastric Acid Reducing Agents: No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with esomeprazole, a proton pump inhibitor. Strong CYP3A Inhibitors: Coadministration of a single 5 mg oral dose of crizotinib with ketoconazole, a strong CYP3A inhibitor, increased crizotinib AUC -INF by 26% and C max by 44% compared to crizotinib alone. Coadministration of XALKORI 25 mg orally once daily with itraconazole, a strong CYP3A inhibitor, increased crizotinib steady-state AUC by 57% and C max by 33% compared to crizotinib alone [see Drug Interactions (7.)]. Strong CYP3A Inducers: Coadministration of XALKORI 25 mg orally twice daily with rifampin, a strong CYP3A inducer, decreased crizotinib steady-state AUC -Tau by 84% and C max by 79%, compared to crizotinib alone [see Drug Interactions (7.)]. CYP3A Substrates: Coadministration of XALKORI 25 mg orally twice daily for 28 days increased AUC -INF of oral midazolam (CYP3A substrate) 3.7-fold compared to midazolam alone [see Drug Interactions (7.2)]. In Vitro Studies CYP Enzymes: Crizotinib inhibits CYP2B6 in vitro. Crizotinib does not inhibit CYPA2, CYP2C8, CYP2C9, CYP2C9, or CYP2D6. Crizotinib does not induce CYPA2, CYP2B6, CYP2C8, CYP2C9, CYP2C9, or CYP3A. UDP-glucuronosyltransferase (UGT): Crizotinib does not inhibit UGTA, UGTA4, UGTA6, UGTA9 or UGT2B7. Transporters: Crizotinib inhibits P-gp, organic cation transporter (OCT), and OCT2. Crizotinib does not inhibit organic anion transporting polypeptides (OATP) B, OATPB3, organic anion transporter (OAT), OAT3, or bile salt export pump transporter (BSEP). 7

18 3 NONCLINICAL TOXICOLOGY 3. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with crizotinib have not been conducted. Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 5 mg/kg/day for 28 days (greater than.7 times the recommended human dose based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 5 mg/kg/day (approximately times the recommended human dose based on body surface area) for 3 days. 4 CLINICAL STUDIES 4. ALK-Positive Metastatic NSCLC Previously Untreated ALK-Positive Metastatic NSCLC - Study (PROFILE 4; NCT544) The efficacy of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study ). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version. as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, duration of response (DOR), and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment. Patients were randomized to receive XALKORI (n=72) or chemotherapy (n=7). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (-, 2), race (Asian, non-asian), and brain metastases (present, absent). Patients in the XALKORI arm received XALKORI 25 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 5 mg/m 2 with cisplatin 75 mg/m 2 or carboplatin AUC of 5 or 6 mg min/ml by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI. The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status or (95%), 5% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. At 8

19 the time of the final analysis of overall survival, 84% of patients randomized to the chemotherapy arm subsequently received XALKORI. Study demonstrated a statistically significant improvement in PFS in patients treated with XALKORI. There was no statistically significant difference in OS between patients treated with XALKORI and patients treated with chemotherapy. Table 7 and Figure summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment. Table 7. Previously Untreated ALK-Positive Metastatic NSCLC - Efficacy Results in Study XALKORI (N=72) Chemotherapy (N=7) Progression-Free Survival (Based on IRR) Number of Events (58%) 37 (8%) Progressive Disease 89 (52%) 32 (77%) Death (6%) 5 (3%) Median, Months (95% CI).9 (8.3, 3.9) 7. (6.8, 8.2) HR (95% CI) a.45 (.35,.6) p-value b <. Overall Survival Number of Events 7 (4%) 8 (47%) Median, Months (95% CI) NR (45.8, NR) 47.5 (32.2, NR) HR (95% CI) a.76 (.55,.5) p-value b.98 Tumor Responses (Based on IRR) Objective Response Rate % (95% CI) 74% (67, 8) 45% (37, 53) CR, n 3 (.7%) 2 (.2%) PR, n 25 (73%) 75 (44%) p-value c <. Duration of Response Median, Months (95% CI).3 (8., 3.8) 5.3 (4., 5.8) HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; NR=not reached; CR=complete response; PR=partial response. a Based on the Cox proportional hazards stratified analysis. b Based on the stratified log-rank test. c Based on the stratified Cochran-Mantel-Haenszel test. 9